Interleukin-2 (IL-2) is a cytokine with important regulatory properties for both T and B cells. The current studies were undertaken to evaluate IL-2 in the treatment of human immunodeficiency virus (HIV) infection. Our studies initially focused on patients with CD4 counts about 200 cells/cu mm, administering IL-2 for 5 days approximately every 2 months at doses ranging from 6 to 18 million units/d. The courses of IL-2 were well tolerated, although most of the patients required dosage reductions due to IL-2-related adverse effects. Sustained improvement in CD4 number was seen primarily in patients with >200 CD4 cells/cu mm. There also was a transient increase in viral load as measured by the bDNA assay seen at day 6 to day 8 following initiation of IL-2 therapy. Responses in CD4 number were less common in patients with lower baseline CD4 counts. Based on the preliminary results seen in our open trial, we undertook a randomized trial to evaluate IL-2 therapy in patients with CD4 counts above 200 cells/cu mm in combination with currently approved antiretroviral therapies. The study opened in April 1993 and was completed in February of 1995, with 60 patients enrolling. This study also showed in a controlled setting that intermittent therapy with IL-2 can lead to a substantial and sustained increase in CD4 cell counts without leading to an increase in plasma viral load. More recently, we have focused on improving the tolerance of IL-2, by decreasing the dose and duration of therapy, and by evaluating alternative methods of administering IL-2. We have been enrolling patients in an extension phase of ongoing studies to determine whether administration of corticosteroids with IL-2 can lead to improved tolerance of IL-2 with-out interfering with the immunomodulatory effects. Preliminary experience has shown that in some patients previously unresponsive to IL-2, improved tolerance of IL-2 when it was coadministered with prednisone has allowed dose escalation of IL-2 and resulted in an increase in CD4 counts. Prednisone is currently being held, however, as we evalu-ate the potential role of steroids in the development of avascular necrosis in HIV-infected patients. These studies are potentially important because they are the first ones to suggest that immunomodulating agents combined with antiretroviral agents may have a benefit in patients with HIV infection.